Dysfunction in volume homeostatic mechanisms inappropriately increases renal sodium reabsorption, leading to volume expansion, salt sensitive blood pressure (SSBP) and consequent hypertension (HTN). This competitive renewal is focused on striatin (STRN) and expands on our published and preliminary data. The OVERALL HYPOTHESES for this proposal are: 1) STRN is a new, novel modulator of two major sodium/volume homeostatic systems when salt intake changes: aldosterone (ALDO) secretion and renovascular vasodilation. 2) On a liberal salt intake, STRN deficiency is associated with dysregulation of both systems resulting in SSBP and increased risk of HTN. These hypotheses are supported by our strong preliminary data focused in two general areas. VASCULATURE: STRN protein levels in heart, vessels and adrenals increase with dietary salt restriction. ? Human hypertensive, and importantly normotensive, STRN risk allele carriers and STRN heterozygous knockout (HET-KO) mice have SSBP with higher BP levels on a liberal salt intake. ? STRN HET-KO vs. WT mice have impaired salt mediated vasodilation, likely secondary to decreased NO- cGMP production and/or effects. Particulate guanylyl cyclase (pGC) and soluble GC (sGC) generate cyclic guanosine mono-phosphate (cGMP) causing vasodilation. ALDOSTERONE: STRN is a critical factor regulating the non-genomic actions of steroid hormones ? Zona glomerulosa (ZG) expression of sGC and pGC is regulated by salt intake. ? ZG expresses the mineralocorticoid receptor (MR), which regulates ALDO production via a novel, ultra- short feedback loop, potentially involving STRN. ? ALDO levels are increased in the STRN HET-KO vs WT mice on a liberal salt diet. Using a translational approach, we will test our overall hypotheses by addressing three AIMS: AIM 1: Hypothesis: the BP in hypertensive individuals who carry the STRN risk allele will be uniquely responsive to MR blockade as compared to hypertensive non-carriers. AIM 2: Hypothesis: STRN modulates ALDO secretion via changes in adrenal cGMP (directly or indirectly through changes in ANP/BNP) and/or the MR mediated adrenal ultra-short feedback loop. Thus, STRN deficiency leads to inappropriately increased ALDO on a liberal salt diet. AIM 3: Hypothesis: STRN mediates cGMP increases in the renal vasculature when salt intake is increased resulting in renovascular vasorelaxation and increased sodium excretion. Thus, when STRN is reduced, cGMP is reduced resulting in impaired liberal salt intake mediated vasorelaxation and thus, inappropriate sodium retention. Thus, we will define how STRN interacts with sodium intake, influences renal function and ALDO and thereby provide entre to valuable new approaches to specifically prevent and/or treat HTN and its consequences.